Clinical Pharmacokinetics

, Volume 47, Issue 3, pp 181–189 | Cite as

Application of Basic Pharmacokinetic Concepts to Analysis of Microdialysis Data

Illustration with Imipenem Muscle Distribution
  • Claire Dahyot
  • Sandrine Marchand
  • Mikael Bodin
  • Bertrand Debeane
  • Olivier Mimoz
  • William Couet
Original Research Article


Background: Microdialysis studies of antibacterial tissue distribution in critically ill patients have sometimes led to results that were spectacular but inconsistent with basic pharmacokinetic concepts.

Objective: To conduct a study of imipenem distribution in the muscle of healthy volunteers and critical care patients in order to compare real-life data with theory.

Methods: Microdialysis catheters were placed into the quadriceps, and probe recoveries were determined individually in vivo using a retrodialysis-by-drug method. Unbound imipenem concentrations were determined by high-performance liquid chromatography in plasma ultrafiltrates and muscle dialysates, and submitted to noncompartmental pharmacokinetic analysis.

Results: Individual unbound imipenem concentrations in plasma and muscle extracellular fluid were virtually superimposed at any time, both in healthy volunteers and in critical care patients.

Conclusion: These new results are not consistent with previously published data obtained in similar conditions by another group, but they are in agreement with results previously obtained in rats, as well as being consistent with basic pharmacokinetic concepts.


Imipenem Unbind Concentration Critical Care Patient Cilastatin Microdialysis Catheter 
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This work was funded by a grant (PHRC) from the French Ministère de l’Education Nationale et de la Recherche. The authors thank Pharsight Corporation (Mountain View, CA, USA) for free supply of WinNonlin 4.0.1 software through the Pharsight Academic License (PAL) program. The authors have no conflicts of interest that are directly relevant to the content of this study.


  1. 1.
    Liu P, Muller M, Derendorf H. Rational dosing of antibiotics: the use of plasma concentrations versus tissue concentrations. Inter J Antimicrob Agents 2002; 19: 285–90CrossRefGoogle Scholar
  2. 2.
    Rowland M, Tozer TN. Small volume of distribution. In: Rowland M, Tozer TN, editors. Clinical pharmacokinetics: concepts and applications. Philadelphia (PA): Lea and Febiger, 1989: 438–50Google Scholar
  3. 3.
    Hammarlund-Udenaes M, Paalzow LK, De Lange ECM. Drug equilibration across the blood-brain barrier: pharmacokinetic considerations based on the microdialysis method. Pharm Res 1997; 14: 128–33PubMedCrossRefGoogle Scholar
  4. 4.
    Chenel M, Marchand S, Dupuis A, et al. Simultaneous central nervous system distribution and pharmacokinetic-pharmacodynamic modelling of the electroencephalogram effect of norfloxacin administered at convulsant dose in rats. Br J Pharmacol 2004; 142: 323–30PubMedCrossRefGoogle Scholar
  5. 5.
    Karjagin J, Lefeuvre S, Oselin K, et al. Pharmacokinetics of meropenem determined by microdialysis in the peritoneal fluid of patients with severe peritonitis associated with septic shock. Clin Pharmacol Ther. Epub 2007 Aug 8Google Scholar
  6. 6.
    Liu P, Derendorf H. Antimicrobial tissue concentrations. Inf Dis Clin North Am 2003; 17: 599–613CrossRefGoogle Scholar
  7. 7.
    Brunner M, Derendorf H, Muller M. Microdialysis for in vivo pharmacokinetic/pharmacodynamic characterization of anti-infective drugs. Curr Opin Pharmacol 2005; 5: 495–9PubMedCrossRefGoogle Scholar
  8. 8.
    de la Peña A, Dalla Costa T, Talton JD, et al. Penetration of cefaclor into the interstitial space fluid of skeletal muscle and lung tissue in rats. Pharm Res 2001; 18: 1310–4CrossRefGoogle Scholar
  9. 9.
    Huang Y, Ji P, Inano A, et al. Microdialysis studies of the middle ear distribution kinetics of amoxicillin in the awake chinchilla. J Pharm Sci 2001; 90: 2088–98PubMedCrossRefGoogle Scholar
  10. 10.
    Brunner M, Pernerstorfer T, Mayer BX, et al. Surgery and intensive care procedures affect the target site distribution of piperacillin. Crit Care Med 2000; 28: 1754–9PubMedCrossRefGoogle Scholar
  11. 11.
    Tegeder I, Schmidtko A, Bräutigam L, et al. Tissue distribution of imipenem in critically ill patients. Clin Pharmacol Ther 2002; 71: 325–33PubMedCrossRefGoogle Scholar
  12. 12.
    Standiford HC, Drusano GL, Bustamante CI, et al. Imipenem coadministered with cilastatin compared with moxalactam: integration of serum pharmacokinetics and microbiologic activity following single-dose administration to normal volunteers. Antimicrob Agents Chemother 1986; 29: 412–7PubMedCrossRefGoogle Scholar
  13. 13.
    Elmquist W, Sawchuk R. Application of microdialysis in pharmacokinetic studies. Pharm Res 1997; 14: 267–88PubMedCrossRefGoogle Scholar
  14. 14.
    Marchand S, Dahyot C, Lamarche I, et al. Microdialysis study of imipenem distribution in skeletal muscle and lung extracellular fluids of noninfected rats. Antimicrob Agents Chemother 2005; 49: 2356–61PubMedCrossRefGoogle Scholar
  15. 15.
    Dahyot C, Marchand S, Pessini GL, et al. Microdialysis study of imipenem distribution in skeletal muscle and lung extracellular fluids of Acinetobacter baumanii-infected rats. Antimicrob Agents Chemother 2006; 50: 2265–7PubMedCrossRefGoogle Scholar
  16. 16.
    Marchand S, Dahyot C, Lamarche I, et al. Lack of effect of experimental hypovolemia on imipenem muscle distribution in rats assessed by microdialysis. Antimicrob Agents Chemother 2005; 49: 4974–9PubMedCrossRefGoogle Scholar
  17. 17.
    Mouton JW, Touzw DJ, Horrevorts AM, et al. Comparative pharmacokinetics of the carbapenems: clinical implications. Clin Pharmacokinet 2000; 39: 185–201PubMedCrossRefGoogle Scholar
  18. 18.
    Rodloff AC, Goldstein EJ, Torres A. Two decades of imipenem therapy. J Antimicrob Chemother 2006; 58: 916–29PubMedCrossRefGoogle Scholar

Copyright information

© Adis Data Information BV 2008

Authors and Affiliations

  • Claire Dahyot
    • 1
    • 2
  • Sandrine Marchand
    • 1
    • 2
    • 3
  • Mikael Bodin
    • 2
  • Bertrand Debeane
    • 2
    • 3
  • Olivier Mimoz
    • 1
    • 2
    • 3
  • William Couet
    • 1
    • 2
    • 3
  1. 1.Inserm ERI-23PoitiersFrance
  2. 2.CHU PoitiersPoitiersFrance
  3. 3.UFR Médecine-PharmacieUniversité de PoitiersPoitiersFrance

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